Cytosine arabinoside (ara-C) is an S-phase active antineoplastic agent used in the treatment of several hematologic malignancies. We did a retrospective analysis on 48 patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) who were treated with high-dose ara-C between 1982 and 1987. All patients received between 9 and 24 g/m2/course of treatment with 90% receiving 12g/m2/treatment. Fifteen patients (25%) achieved a complete or partial remission. Of these, five (10%) were complete responders. Long-term disease-free survival was maintained only in those responders who were consolidated with autologous bone marrow transplantation. Toxicity was primarily myelosuppression. Seventy-five percent of patients developed fever and neutropenia with an equivalent percent having severe thrombocytopenia sufficient to require platelet transfusion. Five patients (10%) had significant neurotoxicity. There were seven treatment-related deaths (15%). Patients in whom tumors contained a small cell component responded better than patients with purely large cell or undifferentiated lymphomas (50% versus 15%, P = 0.024). We conclude that high-dose ara-C given as 3g/m2 every 12 hours for four doses has a limited role when used as a single agent in the treatment of relapsed or refractory non-Hodgkin's lymphoma. However, there are subsets of patients who may respond favorably to this therapy.